Diamino alkanols and alkanones



United States *Patent p 2,937,185 DIAMINO ALKANOLS ALKANONES John H.Biel, Milwaukee, Wis.,- assignor, by mesne assignments, toLakesideLaboi-atories, Inc, a corporation of Delaware No Drawing.Application August 1'3, 1956 Serial No. 603,803

2 Claims. (Cl. 260- 3265) This invention relates to novel processes ofproducing chemical compounds and the novel compounds so produced. a V

It has been discovered according to the present Invention thatdisubstituted amino alkynes of the formula.

OH Rs N( H2)n+1 H( H2) ..N R; R4

wherein, in each occurrence, m is an integer greater than 0, nis aninteger greater than 1, and R R R and R are the same or different alkylgroups, preferably lower alkyls; aryl groups, preferably monocyclic arylgroups; aralkyl groups, preferably a lower alkyl-monocyclic aryl groups;

cycloalkyl groups, preferably of 6 carbons or less; alkenyl groups,preferably lower alkenyl groups; cycloalkyl-alkyl groups, preferablylower alkyl-monocyclic lower alkyl groups such as of 6 carbons or less;heterocyclic groups such as 2-furfuryl, Z-tetrahydrofurfuryl,Z-thienylmethyl and other heterocyclic groups preferably of 6 atoms orless in the ring; and groups where R and R and/ or R and R are joined sothat the nitrogen is part of a heterocyclic group such as piperidino,morpholino, pyrrolidino, l,2,3,4- tetrahydroisoquinolino,1,2,3,4-tetrahydroquinolino, isoindolino and 4-methyl-l-piperiazino. Itis preferred that m and n each be 10 carbons or less.

The disubstituted amino alkynes used as starting materials may besymmetrical or unsymmetrical, i.e., the carbon to carbon unsaturationneed not be centrally located. Both symmetrical and unsymmetricaldisubstituted amino alkynes may be produced by reacting a metal salt ofan appropriate teritary aminoalkyne with an appropriate tertiaryaminoalkyl halide in an inert solvent as is more fully disclosed in mycopending application, Serial No. 468,137, filed November 10, 1954, nowPatent No. 2,830,048. Bis (N-disubstituted aminoalkyl) 'acetylenes of atleast 6 carbons which may also be used as starting materials may beproduced by reacting a dimetal acetylide with two moles of a teritaryaminoalkyl halide as is more fully described in my copendingapplication, Serial No. 579,162, filed April 19, 1956, now abandoned.Representative compounds which may be used as reactants are1,6-bis(N-dimethylamino)-3-hexyne, 1,6-bis-pyrrolidino-3-hexyne, 1,6-bismorpholino-El-hexyne, l,6- bis piperidino-B-hexyne and similar compoundsin which the alkyne is symmetrically as sulfuric acid. Catalytic amountsof a mercury salt such as mercuric oxide or mercuric sulfate are addedto the mixwith catalysts suchas palladium, platinum and the'oxidesi 2arranged, such as octynes, decynes and the like, 1,5-bis(N-dimethylamino)-2-pentyne, 1,5 bis(N diethylamino)-2- pentyne, 1,6-bispyrrolidino-Z-hexyne, 1,6-bismorpholino- Z-hexyne,1,6-bis(N-diisopropylamino)-2-hexyne, 1,6-bis (N-diethylamino)-2-hexyne, 1- (N-methylpropylamino -8- morpholino 2 octyne, l (Ndiallylamino) l0 (N'- dimethylamino) -2-decyne, 1,6-bis(N-dicyclohexylamino) 3-hexyne, l-(Ndiphenylamino)-5!(N-dibenzylamino)-2- pentyne, and 1,6-bis[N-di(2-furfuryl) amino] -3 -hexyne.

The first step of the overall reaction in which an alkyne is hydrated tothe corresponding alkanol may be conveniently eliected by contacting thealkyne with an aqueous or lower alcohol solution of a mineral acid suchture to promote the hydration. Elevated temperatures such as the refluxtemperature are preferred. After the reaction is terminated the diaminoalkanone may be recovered from the reaction mixture by alkalizingit andthen extracting with an inert immiscible solvent such asether. Theproduct is isolated by evaporation of the extracting solvent. Ifsufliciently stable it may be purified by fractional distillation.

The keto group introduced by the hydration will be located on either ofthe two carbons which formed the unsaturated bond. It cannot bepredicted to which carbon the keto group will go, except in the caseofcornpletely symmetrical reactants, since the remaining part' of themoleculeexerts a directing'influence which may shift its position ofintroduction from one carbon to the other between analogous compounds.Thus, 1,6-bis(N-diethyl-' amino)-2-hexyne gives 1,6--bis(N-diethylamino)-3-hexanone while l,6-bis(N-diethylamino)-3-hexynealso gives 1,6-bis (N-diethylamino) -3-hexanone. The position which theketo group takes is readily determined by those skilled in the art. Withunsymmetrical alkynes there seems to be a tendency for the keto group tobe located on the carbon of the alkyne bond most removed from theterminal carbons although this may vary, The'fully symmetrical 1,6-

bis(N-diethylamino) -3-hexyne gives 1 l,6-bis(N-diethyl-- amino)-3-hexanone. Also, 1,6-bis (N-pyrrolidino) -3- hexyne yields l-,6-bis(Npyrrolidino)-3-hexanone;

Conversion of these and other related alkanones to the correspondingalkanols may be effected by chemical or catalytic means. Lithiumaluminum hydride and sodium borohydride are particularly suitablechemical reducing agents for this process. The reduction may beconveniently effected by contacting the alkanone with such reducingagents in the presence of an inert solvent such as anhydrous ether,dioxane, methanol and tetrahydrofuran. Moderately elevatedtemperatures'such as up to C. may be used to enhance reaction. Thereaction is terminated usually in a few hours, water added to decomposeexcess reducing agent and the product recovered from the organic phaseby conventional isolation methods such as fractional distillation.Catalytic reductionmay be effected produced.- Hydrochloric acid,sulfuric acid, formic acid,

acetic acid, citric acid, maleic acid and fumaric acid may be usedtoformthe corresponding acid addition salts'. I

Quaternary ammonium saltsare formed by contracting the alkanones andalkanols with alkyl and aralkyl esters of mineral and organic acids suchas methyl bromide,

o-chlorobenzyl iodide, methyl sulfate, benzyl chloride;

propargyl bromide, alkyl iodide and the like, preferably in a suitableorganic solvent.

The nontoxic acid addition salts of the alkanones and alkanols areuseful diuretic agents whereas the non-toxic quaternary ammonium saltsare potent and long-acting hypotensive agents.

The following examples are included to illustrate the preparation ofrepresentative compounds provided by this invention but it is to beunderstood that the invention shall not thereby be restricted to theseembodiments.

EXAMPLE 1 1 ,6-bis(N-dimethylamino) -3-hexan0ne vTo a mixture of 50 cc.of 50% sulfuric acid and 1 gm. of mercuric oxide at 60 C. was added 16.8gm. (0.1 mole) of,l,6-bis(N-dimethylamino)-2-hexyne. The mixture wasstirred at 60 C. for three hours. It was filtered, poured over ice andsaturated with potassium hydroxide. It was extracted three times with 50cc. portions of ethyl ether. After being dried over potassium carbonate,the combined ether extracts were vacuum distilled. The product wascollected at 74-75 C./0.7 mm.; gm., 54% yield.

Analysis.Calcd. for C H N O: 15.04% N. Found:

EXAMPLE 2 1,6-bis(N-dimethylamino) -3-hexan0ne The procedure of Example1 was followed to produce this compound from1,6-bis(N-dimethylamino)-3-hexyne, B.P. 7475 C./O.7 mm. The base wasthen reacted with two equivalents of methyl bromide in isopropyl alcoholto form the bis-methobromide salt; M.P. 255-310 C., yield 80%.

Assay.-Calcd.: 7.45% N, 7.45% CO, 42.59% Br. Found: 8.32% N, 47.58% Br.

EXAMPLE 3 1,6-bis(N-diethylamino)-3-hexan0nel,6-bis(N-diethylamino)-2-hexyne was hydrated as in Example 1 to givethis compound.

The base was converted to the bis-hydrochloride salt; M.P. 168-169 C.,yield 70%.

Assay.Calcd.: 8.88% N, 8.88% CO, 22.53% C]. Found: 8.66% N, 7.95% CO,22.32% Cl.

EXAMPLE 4 l,6-bis(N-diethylamino)-3-hexanone1,6-bis(N-diethylamino)-3-hexyne was hydrated as in Example 1 to givethis compound. The bis-hydrochloride and bis-methobromide salts of thebase when mixed with the corresponding salts of the compound produced inExample 3 gave no mixed melting point depression.

EXAMPLE 5 1,6-bis-pyrrolidino-3-hexanone l,6-bis(N-pyrrolidino-3-hexynewas hydrated as in Example 1 to form this base. The bis-hydrochloridesalt had a melting point of 176-177 C., yield 73%.

Assay.Calcd.: 9.00% N, 9.00% CO, 22.82% Cl. Found: 8.82% N, 7.20% CO,22.35% Cl.

EXAMPLE 6 1,6-bis(N-diethylamino)-3-hexanol To 3.8 gm. of sodiumborohydride in 100 cc. of methanol at 60 C. was added 47 gm. ofl,6-bis(N-diethylamino)-3-hexanone. The mixture was heated on a steambath for 1 hour, poured over ice and acidified to pH 2-3 withconcentrated hydrochloric acid. It was concentrated to dryness and theresidue dissolved in 150 cc. ofwater. It was saturated with potassiumhydroxide and extracted with three 100 cc. aliquots of ethyl ether. Theether extracts were dried over potassium carbonate and Found EXAMPLE 7 1,6-bis(N-dimethylam ino -3-hexan0l 1,6-bis(N-dimethylamino)-3-hexanonewas reduced as in Example 6 to for the alcohol; B.P. 65-67 C./0.3 mm.,yield 79% Assay.-Calcd.: 14.89% N. Found: 14.60% N.

The bis-methobromide salt had a melting point of 270-271 C., yield 92%.

Assay.Calcd.: 7.41% N, 42.34% Br. N, 42.53% Br.

Found: 7.57%

EXAMPLE 8 1,5-bis(N-dimethylamino) -3-pentanol By reducing 1,5-bis(N-diethylam'mo) -2-pentanone as in Example 6 this compound wasproduced; B.P. 123-125 C./10 rrnn., 53% yield.

Assay.-Calcd.: 12.17% N. Found: 11.85% N.

The bis-methobromide salt had a melting point of 252-254 C., 60% yield.

Assay.-Calcd.: 6.66% 6.72% N, 37.97% Br.

The bis-hydrochloride salt had a melting point of 201- 202 C., yield96%.

Assay.--Calcd.: 9.24% N, 23.43% Cl. Found: 9.26% N, 23.19% Cl.

N, 38.09% Br. Found:

EXAMPLE 9 1,6-bis-pyrrolidino-3-hexan0l By reducing1,6-bis-pyrrolidino-3-hexanone as in Example 6 this compound Was formed,B.P. 131-133 C./0.1 mm., yield 79%.

Assay.-Ca1cd.: 11.66% N. Found: 11.41% N.

The bis-methobromide salt had a melting point of l82-184 C., yield 94%.

Assay.-Calcd.: 6.51% N, 37.20 Br. Found:'6.41% N, 36.94% Br.

Various changes and modifications of the invention can be made and, tothe extent that such variations incorporate the spirit of thisinvention, they are intended to be included within the scope of theappended claims.

What is claimed is:

1. The process which comprises reacting a compound of the formulaN-(cH,)..o=O(oH,),..N R: BA

with a hydrating agent to produce a compound of the formula andcontacting said compound with a reducing agent to produce a compound ofthe formula R OH I N-(CHa) n+1-CH-(OH2) "t -N wherein m and n areintegers other than Zero but n plus m is at least 3 and not greater than8, and R R R and R are members of the group consisting of phenyl,furfuryl, phenyl-lower alkyl, cyclohexyl, and lower alkenyl groups andthe groups also represent heterocyclic groups of the group consisting 6References Cited in the file of this patent UNITED STATES PATENTS808,747 Hoffman Jan. 2, 1906 1,790,042 Eisleb Ian. 27, 1931 1,845,403Eisleb Feb. 16, 1932 2,046,720 Bottoms July 17, 1936 OTHER REFERENCESGaylord: Reduction with Complex Metal Hydrides,

1956, pp. 124 and 283.

Morgenstern et al.: Chem. Abstracts, vol. -5, p. 1745 (1911).

'Delabyz Chem. Abstracts, vol. 18, p. 70 (1924).

Copp: Chem. Abstracts, cols. 12051-52 (1954).

1. THE PROCESS WHICH COMPRISES REACTING A COMPOUND OF THE FORMULA
 2. THEPROCESS WHICH COMPRISES REACTING 1,6-BIS-PYRROLIDINO-3-HEXYNE WITH AHYDRATING AGENT TO PRODUCE 1,6-BIS-PYRROLIDINO-3-HEXANONE AND CONTACTINGSAID KETONE WITH A REDUCING AGENT TO PRODUCE1,6-BIS-PYRROLIDINO3-HEXANOL.